Electrical excitability in vascular smooth muscle: from rare disease to new paradigms Excitability of vascular smooth muscle (VSM), and hence vascular tone, is controlled by a constellation of ion channels. Despite this decades-old recognition, and isolated examples of primary consequences of ion channel manipulation, both short- and long-term pathophysiological consequences of altered VSM electrical excitability remain poorly understood, or investigated. Here, I propose a series of studies which build from my post- doctoral training in which I have documented complex cardiovascular (CV) abnormalities arising from over- activity of VSM ATP-sensitive potassium (KATP) channels in mouse models of Cantu Syndrome (CS). These models provide a unique opportunity to dissect the systemic mechanisms that link VSM hypo-excitability to cardiac remodeling, pulmonary hypertension, and patent ductus arteriosus, as well as to determine the potential for pharmacological blockade (with sulfonylurea drugs) to reverse these CV abnormalities. As there is currently no targeted therapy for CS, these studies have clear translational impact and serve as a vital pre- clinical test for the repurposing of KATP inhibitors for CS, specifically, and potentially for CS-related CV abnormalities more generally - such as PDA. I hypothesize that CS represents a defining example of the pathophysiological CV consequences of decreased VSM excitability, which I will test in additional genetically modified mouse models in which TMEM16A and TRPP1 channels are specifically knocked-out in smooth muscle. These studies have the potential to establish a new paradigm for the long-term, complex effects of decreased electrical excitability in VSM. CV abnormalities in CS overlap strikingly with those observed in high- output heart failure and I hypothesize that decreased electrical excitability in VSM is an unrecognized primary predisposing substrate for cardiac failure, which will be tested here. This project requires me to incorporate a wide range of techniques, from cellular electrophysiology, to physiological approaches at the cellular, organ and whole animal level. By combining my prior experience in ion channel biophysics and electrophysiology, training in relevant techniques for the study of CV physiology, and the establishment of experimental models and approaches, I will be fully equipped to carry out future studies of cellular excitability in the CV system in health and disease.